Our current studies have evolved from a series of experiments conducted during the past ten years which have explored the complex interaction between the differential utilization of carbohydrate and ketone bodies as energy sources for cerebral metabolism. It has been known that epileptic seizures improve during acute periods of fasting or by the chronic ingestion of a ketogenic diet. Our investigations have focused on the delineation of the metabolic perturbations within brain tissue consequent upon the systemic ketosis. It appears that the availability of adequate concentrations of glucose and ketone bodies in the blood is the fundamental governing factor determining whether these metabolic fuels will be oxidized by the brain. We are continuing to characterize the intracellular metabolic fate of ketone bodies after entering brain and the cerebral control mechanisms modulating the differential utilization of these two fuels. Most of these studies have been carried out in vivo utilizing laboratory animals or in vitro utilizing cerebral slice preparations or cultured cells of neural origin. Inevitably, these studies have focused our attention on the enzymes involved in pyruvate metabolism (pyruvate dehydrogenase complex and pyruvate carboxylase), and in ketone body metabolism (beta-hydroxytutyrate dehydrogenase, 3-Oxoacid-CoA transferase and acetoacetyl-CoA thiolase). This ramification from our original studies has increased our involvement in various human conditions associated with a disturbance in pyruvate metabolism including subacute necrotizing encephalomyelopathy (Leigh disease) and the various inherited syndromes associated with ataxia.